Substrates, particularly medical devices, provided with bio-active/biocompatible coatings

ABSTRACT

Disclosed is a method of enhancing the biocompatibility of a substrate by providing the substrate with a continuous bio-active surface coating. This method includes applying to the substrate a first coating which includes an aqueous dispersion or emulsion of a polymer containing an organic acid functional group and an excess of a polyfunctional cross-linking agent which is reactive with the organic acid groups of the polymer. A continuous bio-active surface coating is then formed over the dried first coating by applying thereover a bio-active agent containing an organic acid functional group or metal salt thereof. The first and second coatings are then dried to covalently bond the organic acid functional groups of the bio-active agent to the polymer through the excess unreacted polyfunctional cross-linking agent.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of currently U.S. Ser. No. 08/877,825,filed on Jun. 18, 1997 U.S. Pat. No. 5,869,127, which is acontinuation-in-part of U.S. Ser. No. 08/392,141, filed Feb. 22, 1995U.S. Pat. No. 5,702,754, and herein incorporated by reference.

FIELD OF INVENTION

This invention relates generally to bio-active substrate coatings. Moreparticularly, the present invention relates to a method for providing amedical device or a part thereof with a bio-active coating whichenhances the antithrombogenic nature of such a device without the use ofsolvents and/or the need for high temperature curing. Coatings anddevices incorporating such coatings are also described.

BACKGROUND OF THE INVENTION

It is generally known to provide a substrate, such as a medical deviceor parts of such a device with bio-active coatings for the purpose ofenhancing the bio-compatibility of the device when it is introduced intoa mammal, such as a human body.

Endoprostheses used for minimally invasive procedures in body conduits,such as, for example, in blood vessels may be provided with bio-activecoatings. Vascular grafts, stents and graft-stent combinations arespecific examples of such endoprostheses. Other useful devices includecatheters, guide wires, trocars, introducer sheaths and the like.

Medical articles or devices coated with hydrophilic coatings have beendescribed in a number of references, some of which are discussed below.These patents all employ the use of solvents and/or the requirement forhigh temperature curing.

U.S. Pat. No. 4,119,094 discloses a method of coating a substrate with apolyvinylpyrrolidone-polyurethane interpolymer. In this method, apolyisocyanate and a polyurethane in a first solvent, such as, methylethyl ketone are applied to a substrate. The first solvent is thenevaporated and polyvinylpyrrolidone in a second solvent is applied tothe treated substrate. The second solvent is then evaporated.

International Patent Applications Nos. PCT/EP92/00918, PCT/EP92/00919and PCT/DK92/00132 disclose methods for providing medical devices havingpolyurethane surfaces with a hydrophilic coating ofpoly(meth)acrylamide. Before application of the hydrophilic coating tothe poly(meth)acrylamide substrate surface, it is treated with acompound having functional groups capable of reacting with thepolyurethane and the poly(meth)acrylamide, respectively. This compoundis typically a di- or higher isocyanate functionality in an organicsolvent.

U.S. Pat. No. 5,272,012 discloses a method for applying a protective,lubricious coating to a surface of a substrate. The coating described bythe '012 patent includes a protective compound, such as a urethane; aslip additive, such as a siloxane; and an optional cross-linking agent,such as a polyflnctional aziridine. The surface of a substrate coatedwith such a composition, however, is not continuously lubricious. Such acoating contains separate physical domains of lubriciousnessinterspersed within a protective matrix, rather than a continuous layerof a lubricious agent.

U.S. Pat. No. 5,037,677 discloses a method of interlaminar grafting ofcontinuous, hydrophilic anti-fogging coatings for acrylic intra-ocularlenses. Such a method is accomplished using at least two laminae whichare not mutually soluble. For example, the '677 patent describespreparing a solution of a copolymer of ethyl methacrylate, butylacrylate and hydroxyethyl methacrylate in an ethoxy ethyl acetateorganic solvent. To this solution is added a molar excess ofpolyisocyanate. This solution is applied to a plexiglass substrate whichis placed in a vacuum oven, where a prepolymer is formed from the twosolutes while the ethoxyethyl acetate solvent is evaporated. A 0.2%sodium hyaluronate solution is then applied to the surface of theplexiglass. The plexiglass is then returned to an oven wherein thehydroxyl groups of the Na-hyaluronate react with the isocyanate groupsin the prepolymer layer. Coatings formed in such a manner as the '677patent suffer from the drawback that organic solvents and/or other toxicchemicals are used as carriers which, if not completely removed prior tointroduction of the substrate into the body, can deleteriously react invivo to cause inflammation, blood clotting and other undesirable sideeffects. Thus, in order to avoid the use of such organic solvents, somenon-solvent methods have been developed.

For example, EP Patent Application Nos. 92100787.8 and EP 0 496 305 A2disclose methods for preparing a shaped medical article with a lubricouscoating. In these methods, a coating composition that includes a blendof polyurethane and polyvinylpyrrolidone is co-extruded with a substratepolymer to produce a shaped article having on a surface thereof a layerof the coating composition which becomes lubricous when contacted withwater.

U.S. Pat. No. 5,041,100 discloses a method for coating a substrate witha mixture of poly(ethylene oxide) and an aqueous dispersion of astructural plastic material, e.g. polyurethane. As an example, thispatent discloses a non-cross-linked admixture of poly(ethylene oxide)and a structural plastic material. This composition provides ahydrophilic character to the substrate which may leach to the surfacethereof, or be entrapped adjacent to the surface to provide ahydrophilic, reduced friction character thereto, particularly whenhydrated.

The methods in the above-described references suffer from the drawbackthat inter-polymer networks which physically attach hydrophilic polymersto their substrates often break down upon prolonged turbulent flow orsoaking. Furthermore, the hydrophilic species are weakly attached totheir substrates and can be easily washed away, thereby rendering theunderlying article insufficiently lubricous.

International Pat. Application No. PCT/DK91/00163, co-owned with thepresent invention, discloses a method of providing a medical instrumentwith a hydrophilic, low-friction coating. This method includes the stepsof (1) forming an inner layer on the substrate from an aqueous polymeremulsion, (2) forming an outer layer on top of the inner layer from anaqueous solution of a water-soluble hydrophilic polymer and (3) curingthe two layers simultaneously by heating to a temperature above 100° C.

Although the use of organic solvents is eliminated in this method, highcuring temperatures must be applied to bond the inner layer to the outerlayer. These high curing temperatures are not useful on heat-sensitivematerials, as well as, heat-sensitive biomolecules. Thus, heat-sensitivesubstrates, such as poly(ethylene terephthalate) (PET) balloon catheterscannot be used with this material. Moreover, molecules such as nucleicacids, proteins, peptides, hormones, heparin and the like areheat-sensitive biomolecules which cannot be exposed to such hightemperatures without losing their activity.

The art is not limited, however, to medical devices having lubriciouscoatings disposed on a surface thereof. Rather, medical articles ordevices coated with bio-compatible or bio-active agents have also beendescribed, some of which are set forth below. All of these patentsemploy various inefficient and/or harsh methods for attaching thebio-compatible/bio-active agent to the surface of a medical article.

For example, U.S. Pat. No. 5,541,167 describes a thrombo-resistant anddefoaming coating for blood contacting surfaces including bubbleoxygenators, blood filters, etc. This coating includes a commercialpreparation of polydimethylsiloxane and silicon dioxide and aquarternary ammonium complex of heparin, such as stearyldimethylbenzyl.This coating, however, suffers from the drawback that the defoaming andheparin components are dissolved in an organic solvent, such asmethylene chloride. Such solvents can denature and reduce thebio-activity of bio-active agent, such as heparin. Furthermore, suchorganic solvent systems produce environmentally hazardous waste, as wellas attacking certain polymer substrates.

In a different approach to rendering an implantable medical devicebio-compatible, U.S. Pat. No. 5,360,397 describes a porousbio-compatible and bio-stable polyurethane mesh for a catheter made frompolycarbonate urethane. This mesh is sputter coated and/or impregnatedwith a bio-active agent, such as for example, a bactericide. A cathetertreated in such a manner, however, is imparted with transientbio-activity at best because the bio-active agent is not covalentlybound to the surface thereof. Furthermore, the process of making such acatheter is inefficient because the porous polyurethane mesh must beattached to the surface of the catheter prior to the application of thebio-active agent.

Still further, U.S. Pat. No. 5,263,992 describes a medical device havinga bio-compatible coating which includes a bio-compatible agent, such asfor example, heparin or streptokinase and a chemical linking moiety.This chemical linking moiety has a structure represented by: A-X-B,wherein A is a photochemically reactive group, B is a reactive groupwhich responds to a different stimulus than A and X is a non-interferingskeletal moiety, such as a C₁ -C₁₀ alkyl. The bio-compatible agent iscovalently linked to the surface of the medical device via the linkingmoiety. In particular, the photochemically reactive group (A) whenactivated covalently binds to the surface of the medical device. Theremaining unreacted reactive group (B) when activated covalently bindsto the bio-compatible agent and anchors it to the surface of the medicaldevice. Such devices, however, are difficult and inefficient to producebecause they require the use of two separate stimuli to activate the Aand B groups of the chemical linking moiety, respectively. Furthermore,the UV light used to activate the A group of the chemical linking moietyfor covalently binding it to the surface of a medical device candenature bio-active agents. Such denaturization reduces the bio-activityof such agents and can result in undesirable medical outcomes, such as,clot formation in the case of an anti-thrombogenic agent.

The present invention, however, is directed to a method of providing asubstrate, particularly a medical device, or a part of such device,intended for introduction in the human body, with a bio-active coatingwhich enhances the bio-compatibility of the substrate. This method isparticularly advantageous because it makes it possible to coat deviceswhich are sensitive to high processing temperatures, such as (PET)balloon catheters and other polymeric or heat sensitive materials orbiomolecules. Moreover, the present invention discloses the use oftwo-component bio-compatible coatings which are both aqueous based. Suchcoatings are mutually soluble and do not pose the increased medicalrisks associated with coatings containing organic solvents. Furthermore,preparation of the present aqueous coatings is more efficient becausevacuum baking substrates is not required as there are no organicsolvents that must be removed. Moreover, because the bio-active surfaceis covalently bonded to the polymer of the first coating, this coatingis permanently attached to the substrate unlike certain of the transientcoatings discussed above.

In summary, the prior art methods suffer from the drawback that they useorganic solvents in their coating layer and/or cure at hightemperatures, are transient or inefficient to produce. Thus, there is aneed for improved bio-active agentibio-compatible coatings which enhancethe compatibility and abrasion-resistance of the surface of heatsensitive medical devices. In particular, there is a need for improvedcompositions and devices which have antithrombogenic properties and moreefficient methods of providing same. The present invention is directedto meeting these and other needs.

SUMMARY OF THE INVENTION

In one embodiment of the present invention there is provided a method ofenhancing the biocompatibility of a substrate by providing the substratewith a continuous bio-active surface coating. This method includesapplying to the substrate a first coating which includes an aqueousdispersion or emulsion of a polymer containing an organic acidfunctional group and an excess of a polyfunctional cross-linking agentwhich is reactive with the organic acid groups of the polymer. Thiscoating is then permitted to dry in order to cross-link and render thefirst coating substantially water-insoluble. Excess unreactedpolyfunctional cross-linking agent remains present in the cross-linkedfirst coating. A continuous bio-active surface coating is then formed onthe first coating by contacting the dried first coating layer with asecond coating of an aqueous solution or dispersion of a bio-activeagent or a derivative thereof which contain an organic acid functionalgroup or metal salt thereof. The first and second coatings are thendried to covalently bond the organic acid functional groups of thebio-active agent to the polymer through the excess unreactedpolyfunctional cross-linking agent.

In another embodiment of the present invention, there is provided amedical device having a bio-active coating on at least a portion of asurface thereof. This bio-active coating includes a first substantiallywater-insoluble coating layer formed from an aqueous dispersion oremulsion of an organic acid functional group-containing polymer and anexcess of a polyfunctional cross-linking agent which is reactive withthe organic acid groups on the polymer. This composition also includes asecond coating of an aqueous solution or dispersion of a bio-activeagent or its derivative which contain an organic acid functional groupor metal salt thereof. The first coating is covalently bonded to thesecond coating through reaction of the excess cross-linking agent andthe organic acid functional groups on the bio-active coating.

In a further embodiment of the present invention there is provided abio-active coating composition for rendering substrates bio-compatible.This composition includes an aqueous dispersion or emulsion of anorganic acid functional group-containing polymer and an excess of apolyfunctional cross-linking agent which is reactive with the organicacid functional groups of the polymer. This composition also includes anaqueous solution or dispersion of a bio-active agent or its derivativewhich contain an organic acid functional group or metal salt thereof.The polymer is bonded to the organic acid functional groups on thebio-active agent through the unreacted excess polyfunctionalcross-linking agent.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of the present invention, the term "organic acid functionalgroup" is meant to include any functional group which contains anorganic acidic ionizable hydrogen. Examples of such functional groupsinclude free carboxylic, free sulfonic, and free phosphoric acid groups,their metal salts and combinations thereof. Such metal salts include,for example, alkali metal salts like lithium, sodium and potassiumsalts; alkaline earth metal salts like calcium or magnesium salts; andquaternary amine salts of such acid groups, particularly quaternaryammonium salts.

In the present invention, the organic acid functional group-containingpolymer of the first aqueous coating composition is selected based onthe nature of the substrate to be coated. The polymer in the firstcoating composition may be a homo- or copolymer such as, for example,vinyl monomer units, polyurethanes, epoxy resins and combinationsthereof. These classes are merely exemplary and other polymericmaterials may be found to be useful. Preferably, the polymer in thefirst coating composition may include organic acid functionalgroup-containing polyurethanes, polyacrylates, polymethacrylates,polyisocrotonates, epoxy resins, (meth)acrylate-urethane copolymers andcombinations thereof. More preferably, the polymer in the first coatingcomposition includes homo- and copolymers having a substantial amount oforganic acid functional groups in their structure. Not wishing to bebound by a particular theory, it is believed that the presence oforganic acid functional groups in the polymer act as internalemulsifying agents. A specific class of polyurethanes which are usefulin the first coating are the so-called water-borne polyurethanes.Particularly preferred examples of such polyurethanes are internallyemulsified water-borne polyurethanes containing internal emulsifierssuch as, for example, carboxylic acid, sulfonic acid and/or phosphoricacid groups, including salts of such groups.

Water-borne polyurethanes which are internally emulsified include, forexample, those supplied under the trade name NeoRez by Zeneca Resins,including NeoRez-940, NeoRez-972, NeoRez-976 and NeoRez-981; those underthe trade name Sancure, including Sancure 2026, Sancure 2710, Sancure1601 and Sancure 899 by B.F. Goodrich; and those under the trade namesBayhydrol LS-2033, Bayhydrol LS-2100, Bayhydrol LS-2990 by Bayer AG.

Another example of a type of polymer useful in the first coatingcomposition is the (meth)acrylate-urethane copolymers, including(meth)acrylic urethane copolymer dispersions supplied under the tradenames NeoPac E-106, NeoPac E-121, NeoPac E-130 and NeoRez R-973 byZeneca Resins.

The concentration of the polymer in the first coating is from about 1%to about 60% by weight, and preferably from about 1% to about 40% byweight. These percent weight values are calculated based on the amountof solid polymer compared to the total weight of the first coating.

The first coating also includes one or more polyfunctional cross-linkingagents that are reactive with organic acid functional groups. In thepresent invention, preferred polyfunctional cross-linking agents includepolyfunctional aziridines and polyfunctional carbodiimides.

In the present invention, other cross-linking agents may also be usedwhich include, for example, commercially available preparations sold byZeneca Resins under the trade name NeoCryl CX 100 and those preparationssold by EIT Industries under the trade name XAMA-7. A commerciallyavailable polyfunctional carboimide which is also useful in the presentinvention is Ucarlink XL-29SE, sold by Union Carbide.

Among the polyfunctional aziridines useful in the present invention arethe trifunctional aziridines of the following formula: ##STR1##

Preferably, the cross-linking agent has more than two functional groupsper molecule. Furthermore, the present invention also encompasses acombination of different polyfunctional cross-linking agents.

Not wishing to be bound by a particular theory, it is believed that thefunctional groups on the cross-linking agent serve at least twopurposes. In particular, these groups serve to cross-link the firstpolymeric coating. Additionally, these groups participate in covalentlybonding the second coating to the first coating through reaction withthe excess organic acid functional groups on the bio-active agent. Thus,there must be sufficient functionality in the cross-linking agent, e.g.an excess of cross-linking agent, to accomplish both purposes. Inparticular, there must be a molar excess of cross-linking agent relativeto the first coating to ensure that the first coating is substantiallycross-linked, and that there are enough unreacted functional groups lefton the cross-linking agent to covalently bond the bio-active agent tothe first coating.

One indication that insufficient functional groups from thecross-linking agent are present is the inadequate bonding of the secondlayer to the substrate. This is evidenced by the lack of wear resistanceof substrates treated with such a deficient first coating. Furthermore,such coatings are easily wiped off the substrate to which they areapplied.

The concentration of the cross-linking agent in the first coatingcomposition is in the range from about 0.2% to about 40% by weightsolids content of the first coating, and preferably in the range fromabout 0.5% to about 20% by weight solids content of the first coating.

The first aqueous coating may include other conventional additives, suchas for example, leveling agents, various stabilizers, pH adjustmentagents, fillers, defoaming agents and the like, as long as such agentsare compatible with the intended use of the coated substrate.

The first coating is applied to a substrate by conventional methods,including dipping and spraying. The first coating is then permitted todry to obtain a continuous, substantially water-insoluble coating on thesurface of the substrate. This coating includes functional groups on thecross-linking agent which are reactive with organic acid groups of thefirst coating. This dried first coating is contacted with a secondaqueous coating which includes an aqueous solution or dispersion of anorganic acid functional group-containing bio-active agent. The secondcoating may be applied over the first coating using the same ordifferent techniques as the first coating. The second coating is thenpermitted to dry, thereby covalently bonding the organic acid functionalgroup-containing bio-active agent to the first coating via the excess,unreacted functional groups of the cross-linking agent in the firstcoating. Optionally, the bio-active agent may be incorporated into thefirst coating in a non-covalent manner. The choice of whether tocovalently bond the bio-active agent to the first coating is made withreference to the intended use of the device, the choice of bio-activeagent and the composition of the first coating.

Bio-active agents useful in the present invention may be selected from awide variety of materials provided that they contain at least oneorganic acid functional group in their structure which can react withthe polyfunctional cross-linking agent and still retain bio-activefunction. Furthermore, in the case where a particular bio-active agentdoes not contain at least one organic acid functional group in itsstructure, a derivative thereof containing such an organic acidfunctional group is also encompassed by the present invention. The useand synthesis of such derivatives are within the knowledge of thoseskilled in the art.

Non-limiting classes of useful bio-active agents of the presentinvention include antithrombogenic agents, antibiotic agents, anti-tumoragents, antiviral agents, anti-angiogenic agents, angiogenic agents,anti-mitotic agents, anti-inflammatory agents, angiostatin agents,endostatin agents, cell cycle regulation agents, genetic agents,including hormones, such as estrogen, their homologues, analogs,derivatives, fragments, pharmaceutical salts and mixtures thereof. Otheruseful bio-active agents include for example, viral reactors and growthhormones such as Fibroblast Growth Factor and Transforming GrowthFactor-β, their homologues, analogs, derivatives, fragments,pharmaceutical salts and mixtures thereof. One specific type ofbio-active material useful in the present invention is the class oforganic acid functional group-containing polysaccharides. For purposesof the present invention, such polysaccharides include linear andbranched polymers of monosaccharides. The preferred polysaccharidebio-active agents of the present invention are glycosaminoglycans(hereinafter "GAGs").

Glycosaminoglycans are unbranched polysaccharide chains of repeatingdisaccharide units. One of the repeating disaccharide units is usuallyan amino sugar (N-acetylglucosamine or N-acetylgalactosamine) which canbe sulfated. The second sugar of the disaccharide unit is usually auronic acid, such as for example, glucuronic or iduronic acid. Becausethere are sulfate or carboxyl groups on most of their sugar residues,GAGs are highly negatively charged and are ideal for covalently bondingto the first coating layers via the excess, unreacted functional groupson the cross-linking agent. GAGs which are useful as bio-active agentsin the present invention include, for example, heparin, hirudin, heparinsulfate, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratansulfate, EPA, prostoctein, reopro, integrin, lytic agents includingurokinase and streptokinase, their homologs, analogs, fragments,derivatives and pharmaceutical salts thereof. Other GAG containingmolecules are also contemplated by the present invention, for exampleGAG-containing proteins, such as proteglycans.

Moreover, the bio-active agent of the present invention can also includeorganic acid functional group-containing antibiotics. For purposes ofthe present invention, such antibiotics include penicillins,cephalosporins, vancomycins, aminoglycosides, quinolones, polymyxins,erythromycins, tetracyclines, chloramphenicols, clindamycins,lincomycins, sulfonamides their homologs, analogs, fragments,derivatives, pharmaceutical salts and mixtures thereof.

Additionally, the bio-active agent of the present invention can alsoinclude organic acid functional group-containing anti-tumor agents. Forpurposes of the present invention, such anti-tumor agents includepaclitaxel, docetaxel, alkylating agents including mechlorethamine,chlorambucil, cyclophosphamide, melphalan and ifosfamide;antimetabolites including methotrexate, 6-mercaptopurine, 5-fluorouraciland cytarabine; plant alkaloids including vinblastine, vincristine andetoposide; antibiotics including doxorubicin, daunomycin, bleomycin, andmitomycin; nitrosureas including carmustine and lomustine; inorganicions including cisplatin; biological response modifiers includinginterferon; enzymes including asparaginase; and hormones includingestrogen, tamoxifen and flutamide their homologs, analogs, fragments,derivatives, pharmaceutical salts and mixtures thereof.

Still further, the bio-active agent of the present invention can includeorganic acid functional group-containing anti-viral agents. For purposesof the present invention, such anti-viral agents include amantadines,rimantadines, ribavirins, idoxuridines, vidarabines, trifluridines,acyclovirs, ganciclovirs, zidovudines, foscarnets, interferons theirhomologs, analogs, fragments, derivatives, pharmaceutical salts andmixtures thereof.

In certain cases, such bio-active agents may also become lubricous uponcontact with an aqueous medium. Such lubricity will depend on a numberof factors, including the type of bio-active agent, its molecularweight, the exposure level to the aqueous medium, as well as thepresence of agents which facilitate wetting. In the present invention,the molecular weight of the bio-active agent can vary from fewer than500 for paclitaxel to about 3,000 to about 30,000 for heparin to anexcess of 8,000,000 for hyaluronic acid.

The concentration of the bio-active agent in the second coatingcomposition will typically be from about 0.1% by weight, preferably fromabout 50% by weight, calculated as solids of bio-active agent comparedto the total weight of the second coating composition.

In one embodiment of the present invention, the functional groups of thecross-linking agent react with the organic acid functional groups of thepolymer in the first coating and the organic acid functional groups ofthe bio-active agent at a temperature below 120° C. Preferably, thesereactions take place between about 10° C. to about 70° C. The dryingstep for the second coating is chosen based on the substrate and thecompositions used in the first and second coatings. Many bio-activeagents are temperature sensitive and extreme care must be taken inselecting the appropriate drying temperatures with such agents. Forexample, when heparin is the bio-active agent, the drying temperatureshould be no greater than about body temperature.

The selection of the appropriate drying temperature is within the skillof the art given the properties of the substrate and the compositions inthe first and second coatings. Preferably, the drying step takes placewell below 120° C. If desired, however, and compatible with the natureof the substrate to be coated, higher temperatures may be used, such asfor example, when the substrate is metal. Nevertheless, the presentinvention is designed to be used in coating temperature-sensitivesubstrates. Thus, the first and second coatings are preferably dried atlow temperatures, particularly at ambient or room temperatures, such asfor example, at or between about 15° C. and about 35° C. In many cases,drying at about room temperature for about 12 hours will be adequate.

Obviously, the drying time will depend on the drying temperature used,higher drying temperatures requiring shorter drying times and lowerdrying temperatures requiring longer drying times. As set forth above,it is within the knowledge of a person skilled in the art to determine asuitable combination of drying temperatures and drying times for aspecific coating and substrate.

Furthermore, the organic acid functional groups of the cross-linkingagent do not necessarily have to have the same reactivity towards theorganic acid functional groups of the polymer and bio-active agent inthe first and second coatings, respectively. Moreover, the selection ofdrying conditions will be made with these reactivities in mind.

The bio-active coatings of the present invention may be used to coat awide range of different substrates. In particular, the bio-activecoatings are especially suited for coating at least a portion of asurface of a medical article for use in or on the body, particularlycatheters, guidewires, introducer sheaths, trocars and the like, orparts of such articles. More particularly, these coatings may be used tocoat endoprostheses including for example, grafts, stents andgraft-stent devices. Furthermore, these coatings can be used to coatmany different substrates, such as for example, polymeric substrates,non-polymeric substrates, such as metals, and combinations thereof.

For purposes of the present invention, polymeric substrates which may beused include, for example, olefin polymers, particularly polyethylene,polypropylene, polyvinylchloride, polytetrafluoroethylene (PTFE),polyvinylacetate, and polystyrene; polyesters, particularlypoly(ethylene terephthalate); polyurethanes; polyureas; siliconerubbers; polyamides, particularly nylons; polycarbonates; polyaldehydes;natural rubbers; polyether-ester copolymers such as Hytrel™ and Anitel™;polyether-amide copolymers such as Pebax™; and styrene-butadienecopolymers. Preferably, the polymeric substrate is made frompoly(ethylene terephthalate), polyurethane, polyethylene, nylon 6, nylon11, a polyether-ester copolymer or a polyether-amide copolymer.Shape-memory polymers are also contemplated. The substrate can, ofcourse, be made from other polymers depending upon the intended usethereof and the composition of the first and second coatings. Such achoice of substrate materials is within the knowledge of one skilled inthe art.

As set forth above, non-polymeric substrates may also be used in thepresent invention. These non-polymeric substrates include, for exampleceramics, metals, glasses and the like. Furthermore, the substrates ofthe present invention may include a combination of one or more polymersand/or one or more non-polymers. Examples of metals employed in medicaldevices include, without limitation, stainless steel, superelasticmaterials (shape-memory) such as nitinol, gold, silver, titanium,tantulum, platinum and alloys thereof.

In another embodiment of the present invention, a medical device havinga bio-active coating on at least a portion of a surface thereof isprovided for use in conjunction with a body. The bio-active coatingincludes a first substantially water-insoluble coating layer formed froman aqueous dispersion or emulsion of an organic functionalgroup-containing polymer and an excess of a polyfunctional cross-likingagent, each of which is described above. As set forth previously, thecross-linking agent is reactive with the organic acid groups of thepolymer.

The bio-active composition also includes a second coating of an aqueoussolution or dispersion which contains an organic acid functionalgroup-containing bio-active agent, as described hereinabove. The firstcoating is covalently bonded to the second coating through the excesscross-linking agent and the organic acid functional groups on thebio-active coating.

In a further embodiment of the present invention, there is provided abio-active coating composition for rendering substrates bio-compatible.This coating composition includes an aqueous dispersion or emulsion ofan organic acid functional group-containing polymer and an excess of apolyfunctional cross-linking agent, each of which is described above.This cross-linking agent is reactive with the organic acid functionalgroups of the polymer. There is also provided an aqueous solution ordispersion of an organic acid functional group-containing bio-activeagent, as previously described. The polymer is bonded to the organicacid functional groups on the bio-active agent through the unreacted,excess polyfunctional cross-linking agent.

The invention will now be further illustrated in the followingnon-limiting examples representing presently preferred embodiments ofthe invention.

EXAMPLE 1

A first coating composition is prepared by adding the followingingredients successively to a glass beaker under proper agitation untilthoroughly mixed.

NeoRez R981: 250 ml

Water: 250 ml

0.5% Fluorad FC-129 stock solution: 10 ml (prepared by diluting 1 mlFluorad FC-129 in 100 ml of water)

34% NH₄ OH: 4 ml

NeoCryl CX 100: 20 ml

NeoRez R98 1 (from Zeneca Resins) is a polyester-based, aliphaticwater-borne polyurethane containing carboxylic acid groups as internalemulsifier, which is stabilized by triethylamine (TEA) and has a solidscontent of 32% and a pH of 7.5-9.0 at 25° C. It contains a 5.3%N-methyl-pyrrolidone as cosolvent. NeoCryl CX 100 (from Zeneca Resins)is a polyfunctional aziridine crosslinking agent. Fluorad FC-129 (from3M) is added as a leveling agent. Anunonium hydroxide is used to adjustthe pH of the solution.

A second coating composition, as follows, is prepared:

1.2% aqueous solution of Sodium Heparin (Abbott): 400 ml

The above solution is prepared by adding an appropriate amount ofheparin powder to water under agitation for several hours to obtain aclear homogeneous solution.

A substrate is prepared by extruding a blend of two grades ofpolyether-ester block copolymer ARNITEL EM 740 and EM630 (from Akzo)with BaSO₄, into a tube. The tube is dipped into the first coatingcomposition prepared above and dried at ambient temperature (roomtemperature) for 40 minutes. Then the tube is dipped in the secondcoating composition and dried at ambient temperature over night to forma continuous coating of the heparin on the surface of the substrate. Thecoated surface shows very good antithrombogenic effect when contactedwith blood. Furthermore, the coating has very good durability whilestill retaining its bio-activity. The coating is strongly retained onthe surface even under the application of strong forces.

EXAMPLE 2

In the same manner as in Example 1, a first coating composition isprepared using the following ingredients:

Sancure 2710: 250 ml

Water: 100 ml

NeoCryl CX 100: 10 ml

Sancure 2710 (from B.F. Goodrich) is an aliphatic polyurethanedispersion containing carboxylic acid groups as internal emulsifier andbeing stabilized by TEA. The dispersion has a solids content of about40%, a pH of 8.3 and a viscosity of 1,000 cps.

A second coating composition is prepared in the same manner as inExample 1:

1.2% sodium heparin (Abbott) aqueous solution

Endoprostheses, including a textile (PET) vascular graft, a vascularstent and a vascular graft-stent combination are each coated with theabove coating compositions in the following manner. The endoprosthesesare coated with the first coating composition by dipping. Theendoprostheses are then dried at ambient temperature for 30 minutes.Next, the prostheses are dipped in the second coating composition anddried at ambient temperature over night. The resultant dried coating issterilized by electron beams at a dose of 2×25 KGray.

The coated endoprostheses each show excellent anti-thrombogenic activityand lubricity when contacted with blood. Furthermore, the coating hasvery good durability while still retaining its bio-activity.

EXAMPLE 3

First and second coating compositions are prepared as described inExample 2, with the exception that heparin sulfate is substituted forheparin in the second coating. Endoprostheses are coated as described inExample 2. The coated endoprostheses show excellent anti-thrombogenicactivity and lubricity when contacted with blood. Furthermore, thecoating has very good durability while still retaining its bio-activity.

EXAMPLE 4

First and second coating compositions are prepared as described inExample 2 except that sodium hyaluronate (hyaluronic acid) issubstituted for heparin in the second coating. Endoprostheses are coatedas described in Example 2. The coated endoprostheses show excellentanti-thrombogenic activity and lubricity when contacted with blood.Furthermore, the coating has very good durability while still retainingits bio-activity.

EXAMPLE 5

First and second coating compositions are prepared as described inExample 2 except that chondroitin sulfate is substituted for heparin inthe second coating. Endoprostheses are coated as described in Example 2.The coated endoprostheses show excellent anti-thrombogenic activity andlubricity when contacted with blood. Furthermore, the coating has verygood durability while still retaining its bio-activity.

EXAMPLE 6

First and second coating compositions are prepared as described inExample 2 except that derrnatan sulfate is substituted for heparin inthe second coating. Endoprostheses are coated as described in Example 2.The coated endoprostheses show excellent anti-thrombogenic activity andlubricity when contacted with blood. Furthermore, the coating has verygood durability while still retaining its bio-activity.

EXAMPLE 7

First and second coating compositions are prepared as described inExample 2 except that keratan sulfate is substituted for heparin in thesecond coating. Endoprostheses are coated as described in Example 2. Thecoated endoprostheses show excellent anti-thrombogenic activity andlubricity when contacted with blood. Furthermore, the coating has verygood durability while still retaining its bio-activity.

EXAMPLE 8

A first coating composition is prepared as described in Example 1 usingthe following ingredients:

Bayhydrol LS-2033: 250 ml

Water: 250 ml

0.5 Fluorad FC-129 stock solution: 10 ml

34% NH₄ OH: 4 ml

NeoCryl CX 100: 20 ml

Bayhydrol LS-2033 (from Bayer A.G.) is a water-borne polyurethane whichis stabilized by sulfonate groups. The water-borne polyurethane assupplied has a pH of 6.5-7.5, and the sulfonate groups are in sodiumsalt form. The polyurethane has a solids content of 40%.

A second coating composition is prepared as described in Example 1 usingthe following ingredients:

Heparin: 400 ml of Sodium Heparin (Abbott) in 1% Versicol WN23

Streptomycin: 1.0 ml of an aqueous solution containing 10,000 Units ofStreptomycin Sulfate

A polyurethane catheter is dipped in the first coating composition anddried in an over at 60° C. for 10 minutes. Then the catheter is dippedin the second coating composition, dried in an oven at 60° C. for 10minutes and dipped in the second coating composition once more, afterwhich it is dried at ambient temperature over night. The coated cathetershows excellent anti-thrombogenicity and antibacterial properties, aswell as, good lubricity when contacted with blood.

EXAMPLE 9

Using the same coating procedures as described in Example 1, a stainlesssteel stent is coated with the following coating compositions.

First coating composition:

NeoPac E121: 250 ml

Water: 100 ml

34% NH₄ OH: 2 ml

NeoCryl CX 100: 16 ml

Second coating composition:

1.0% aqueous solution of Sodium Heparin (Abbot): 400 ml

The coated stent shows excellent anti-thrombogenicity when contactedwith blood.

EXAMPLE 10

Using the same coating procedures as described in Example 1, a PETendoprosthesis is coated with the following coating compositions:

First coating composition:

Bayhydrol LS 2033: 200 ml

NeoRez R-940: 100 ml

Triethylamine: 2 ml

Water: 200 ml

NeoCryl CX 100: 10 ml

Second coating composition:

0.8% sodium heparin (Abbott) aqueous solution: 400 ml

The coated endoprosthesis shows excellent anti-thrombogenicity whencontacted with blood.

EXAMPLE 11

A glass plate is coated with the following coating compositions asdescribed below:

First coating composition:

Sancure 899: 200 ml

NeoPac E121: 100 ml

Acrysol TT-615: 1 ml (prediluted with equal weight of water)

SAG 710: 1 ml

34% NH₄ OH: 4 ml

Second coating composition:

1% Sodium Heparin (Abbott) aqueous solution: 400 ml

The first coating composition is brushed onto the glass plate and driedat ambient temperature for 1 hour. Then, the second coating compositionis sprayed onto the precoated glass surface and dried at ambienttemperature over night. The coated glass shows excellentanti-thrombogenicity when contacted with blood.

Acrysol TT-615 is a thickener available from Rohm and Haas Company, andSAG 710 is a defoaming agent available from OSI Specialties, Inc.

EXAMPLE 12

First coating composition:

Sancure 899: 250 ml

0.5% Fluorad FC-129 stock solution: 10 ml

34% NH₄ OH: 4 ml

Water: 200 ml

Ucarlink XL-29SE: 40 mnl

Second coating composition:

1% sodium heparin (Abbott) aqueous solution: 400 ml

A graft made from polyurethane is dipped in the first coatingcomposition and dried at ambient temperature for 40 minutes. Then, thegraft is dipped in the second coating composition, dried at ambienttemperature for 30 minutes and then dipped in the second coatingcomposition once more. The coating is sterilized by EtO (ethylene oxide)sterilization. The coated graft shows excellent anti-thrombogenicitywhen contacted with blood.

Ucarlink XL-29SE is a polyfunctional carboimide, available from UnionCarbide.

EXAMPLE 13

A PET endoprosthesis is coated with the following coating compositions:

First coating composition:

NeoPac E121: 250 ml

Water: 250 ml

Ucarlink XL-29SE: 40 ml

Second coating composition:

1% sodium heparin (Abbott) aqueous solution: 400 ml

First coating composition: 1 ml

The endoprosthesis is dipped in the first coating composition and airdried for 30 minutes. Then, the precoated endoprosthesis is dipped inthe second coating composition and air dried for 30 minutes followed bydrying at 60° C. for 24 hours. The coated endoprosthesis shows excellentanti-thrombogenicity when contacted with blood.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and, all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A medical device having a bio-active coating onat least a portion of a surface thereof, said bio-active coatingcomprising a first substantially water-insoluble coating layer formedfrom an aqueous dispersion or emulsion of an organic acid functionalgroup-containing polymer and a polyfunctional cross-linking agent,wherein a portion of said polyfunctional cross-linking agent iscovalently bonded to said organic acid groups on said polymer andfurther wherein an excess of said polyfunctional cross-linking agent isnot covalently bonded to said organic acid groups on said polymer, and asecond coating of an aqueous solution or dispersion containing anorganic acid functional group-containing bio-active agent, said firstcoating covalently bonded to said second coating through said excesscross-linking agent and said organic acid functional groups on saidbio-active agent.
 2. The medical device of claim 1, wherein said surfaceis selected from the group consisting of polymeric compositions,non-polymeric compositions and combinations thereof.
 3. The medicaldevice of claim 2, wherein said surface is further selected from thegroup of polymeric compositions consisting of olefin polymers includingpolyethylene, polypropylene, polyvinyl chloride,polytetrafluoroethylene, polyvinyl acetate, polystyrene, poly(ethyleneterephthalate), polyurethane, polyurea, silicone rubbers, polyamides,polycarbonates, polyaldehydes, natural rubbers, polyether-estercopolymers, styrene-butadiene copolymers and combinations thereof. 4.The medical device of claim 3, wherein said surface is further selectedfrom the group of non-polymeric compositions consisting of ceramics,metals, glasses and combinations thereof.
 5. The medical device of claim3, wherein said device is an endoprosthesis.
 6. The medical device ofclaim 5, wherein said endoprosthesis is selected from the groupconsisting of grafts, stents and graft-stent devices.
 7. The medicaldevice of claim 5, wherein said endoprosthesis is selected from thegroup consisting of catheters, guidewires, trocars and introducersheaths.
 8. A bio-active coating composition for rendering substratesbio-compatible comprising an aqueous dispersion or emulsion of anorganic acid functional group-containing polymer and a polyfunctionalcross-linking agent, wherein a portion of said polyfunctionalcross-linking agent is covalently bonded to said organic acid functionalgroups of said polymer and further wherein an excess of saidpolyfunctional cross-linking agent is not covalently bonded to saidorganic acid groups on said polymer, and an aqueous solution ordispersion of an organic acid functional group-containing bio-activeagent or its derivative, said polymer covalently bonded to said organicacid functional groups on said bio-active agent through said unreactedexcess polyfunctional crosslinking agent.